Natural killer (NK) cells use KIR and CD94/NKG2A receptors to detect infected cells and cancer cells that have downregulated MHC class I molecules. Declining NK cell function is associated with infection and poor health in the elderly, but little is know about NK receptor expression or population dynamics in the elderly. OUR LONG-RANGE GOAL is to manipulate NK cells to promote healthy aging. Our CURRENT OBJECTIVE is to study human NK population dynamics and turnover in aging, especially as they relate to age related shifts in NK receptor expression. Supported by our novel preliminary data, our CENTRAL HYPOTHESIS is that an age related change in NK receptor expression is caused by a change in NK development and this in turn alters NK function and turnover. A feature of this shifting balance is the accumulation of NK cells with restricted receptor repertoire. The RATIONALE of the proposed research is that a better understanding of NK population dynamics and shifting NK receptor expression may allow us manipulate innate immunity in healthy and unhealthy aging. Our SPECIFIC AIM is to investigate human NK population dynamics as they relate to KIR and CD94/NKG2 receptor expression and other defined NK subsets. We will 1. test the replication potential and expression of senescence markers in NK subsets with aging, 2. measure turnover rates in KIR+ and NKG2A+ NK cells from young and elderly adult subjects, 3. evaluate the incidence of NK subpopulations with restricted receptor repertoire in young and elderly subjects and will rigorously test whether the NK subpopulations are polyclonal or monoclonal. Our approach is INNOVATIVE. We have documented a reciprocal relationship between NK receptors in aging and we have demonstrated for the first time that NK subpopulations with restricted receptor repertoire are found in healthy elderly people. It is our EXPECTATION that the proposed study will rigorously test our hypotheses and lead to definitive future studies on NK subset development, function, proliferation, and senescence. [unreadable] [unreadable] [unreadable]